Regulation/Role of AcylCer in Normal Epidermis and Atopic Dermatitis

AcylCer 在正常表皮和特应性皮炎中的调节/作用

• 批准号: 8597349
• 负责人: Peter M Elias
• 金额: --
• 依托单位: VETERANS AFFAIRS MED CTR SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-10-01 至 2014-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8597349
• 关键词: Accounting; Acute; Acyl Coenzyme A; Acyltransferase; Address; Adult; Affect; Air; Alcohols; Alleles; Allergens; Allergic rhinitis; Amides; Animals; Asthma; Atopic Dermatitis; Binding; Biochemical; Birth; Bypass; CD4 Positive T Lymphocytes; Ceramides; Chemicals; Childhood; Clinical; Coenzymes; Coupled; Data; Defect; Dermatologist; Development; Disease; Down-Regulation; Eczema; Environment; Enzymes; Epidermis; Esterification; Exposure to; Extracellular Domain; Extracellular Matrix; Extracellular Space; Face; Failure; Family; Flare; Funding; Generations; Genes; Haptens; Heating; Helper-Inducer T-Lymphocyte; Heterogeneity; Homeostasis; Human; Humidity; Hydration status; Hydrolysis; Hydroxylation; Ichthyosis Vulgaris; Immune; Individual; Inflammation; Inherited; Interleukin-4; Irritants; Kininogenase; Knock-in Mouse; LXRalpha protein; Lead; Ligands; Link; Lipase; Lipid Binding; Lipids; Liver; Mechanics; Mediating; Membrane; Metabolic; Metabolism; Mixed Function Oxygenases; Modeling; Molecular; Mus; Mutation; Neonatal; Nuclear Hormone Receptors; Occupational Dermatitis; PPAR alpha; PPAR-beta; Pathogenesis; Patients; Permeability; Peroxisome Proliferator-Activated Receptors; Phenotype; Pilot Projects; Positioning Attribute; Prevalence; Production; Pump; Regulation; Reporting; Research; Role; Serine; Serine Protease; Serine Proteinase Inhibitors; Signal Transduction; Skin; Stratum corneum; Stress; Structural Protein; Structure; Surface; Syndrome; Tail; Tissues; Transgenes; United States National Institutes of Health; Up-Regulation; Vanilloid; Very Long Chain Fatty Acid; Veterans; Water; Waxes; Weight; abstracting; acyl group; alveolar lamellar body; base; cofactor; cohesion; cytokine; enhancer binding protein; env Gene Products; extracellular; filaggrin; improved; insight; kallikrein 4; keratinocyte; keratinocyte differentiation; lipid metabolism; liver function; loss of function mutation; mRNA Expression; microbial; monolayer; mouse model; novel; novel strategies; novel therapeutics; overexpression; pathogen; prevent; public health relevance; receptor; response; restoration; sensor; skin disorder; stressor; surfactant; uptake

DESCRIPTION (provided by applicant): PROJECT SUMMARY/ABSTRACT Lipid-enriched extracellular lamellar membranes in the outermost layer of skin, i.e., stratum corneum (SC), subserve epidermal permeability barrier function, as required for mammalian survival in a dry environment. A family of 10 ceramides (Cer) dominates in these membranes, accounting for about H50% of SC lipid, and therefore H5% of the total weight of SC. Not only their quantities, but also their molecular heterogeneity is required to form lamellar membrane structures. In particular, w-O-acylCer (or acylCer), that contains an acyl group esterified to the w-hydroxy terminal of amide-linked very long-chain fatty acids (>C28), is not only unique to the epidermis, but also critical for normal permeability barrier homeostasis. Importantly, a selective deficiency in acylCer occurs in atopic dermatitis (AD), which could further aggravate inherent defects in SC structures. We showed that inhibition of w-hydroxylation decreases acylCer production, provoking barrier abnormalities, and that mice lacking the normal FA elongase, elongation of very long chain FA (or ELOVL) 4, display a lethal post-natal barrier defect; neither acylCer nor the w-OH Cer covalently-attached to cornified envelope proteins (corneocyte lipid envelope, CLE) are formed in these mice. These acylCer are essential for both extracellular lamellar membrane organization, and for corneocyte lipid envelope formation. We recently showed that both acyl-CoA wax alcohol acyltransferases (AWAT) 1 and CGI-58 (a cofactor of triacylglycerol lipase) are further required for w-O-esterification, leading to acylCer production. Yet, neither the basis for acylCer deficiency in AD, nor the contribution of acylCer deficiency to the pathogenesis of AD is known. We hypothesize that either decreased synthesis or accelerated hydrolysis of acylCer occurs in AD. This biochemical abnormality can be attributed to increased T helper cell 2 (Th2) cytokine-induced downregulation and/or aberrant xeric stress-mediated-signaling of acylCer production via the external humidity and osmotic sensors, TRPV4 and TonEBP, respectively. Together, these signaling defects account for deficiency of acylCer in AD. We will investigate 1) the enzymatic (key enzymes/cofactor, i.e., ELOVL4, w-hydroxylase, AWAT1, and CGI-58) basis for acylCer deficiency as well as the structural/functional consequences of acylCer deficiency in AD; 2) how Th2 cytokines downregulate acylCer in AD; 3) how xeric stress regulates acylCer synthesis via the TRPV4 receptor and/or TonEBP signaling and their alterations in AD; and 4) novel therapeutic strategies for acylCer restoration in AD. PUBLIC HEALTH RELEVANCE: PROJECT NARRATIVE: It is increasingly accepted that a primary barrier defect underlies atopic dermatitis (AD), which displays selective acylceramide (acylCer) deficiency, resulting in increased transcutaneous exposure to allergens which induce AD, and stimulate progression of AD to asthma and allergic rhinitis. The insights gained from the proposed studies will identify novel forms of therapy for AD, a common disease in veterans, based upon normalizing acylCer levels using appropriate metabolic precursors or stimulation of endogenous acylCer production.

描述(由申请人提供)： 项目摘要/摘要哺乳动物在干燥环境中生存所需的皮肤最外层，即角质层(SC)中的富含脂质的细胞外板层膜，可发挥表皮通透性屏障功能。一个由10个神经酰胺组成的家族(Cer)在这些膜中占主导地位，约占SC脂类的H50%，因此占SC总重量的H5%。形成层状膜结构不仅需要它们的数量，而且还需要它们的分子异质性。特别是，w-O-acylCer(或acylCer)，它含有一个酰基，酯化到酰胺连接的超长链脂肪酸(&gt；C28)的w-羟基末端，不仅是表皮所特有的，而且对正常的通透性屏障动态平衡也是至关重要的。重要的是，在特应性皮炎(AD)中会出现酰基Cer的选择性缺陷，这可能会进一步加剧SC结构的固有缺陷。我们发现，抑制w-羟化减少了酰基Cer的产生，引发屏障异常，并且缺乏正常FA伸长酶的小鼠，极长链FA(或ELOVL)4的伸长，表现出致命的出生后屏障缺陷；在这些小鼠中，既没有形成酰基Cer，也没有w-OHCer共价连接到角化的包膜蛋白(角质细胞脂膜，CLE)。这些酰基Cer对细胞外板层膜组织和角膜细胞脂质包膜的形成都是必不可少的。我们最近发现，酰基辅酶A蜡醇酰基转移酶(AWAT)1和CGI-58(三酰甘油脂肪酶的辅助因子)进一步需要进行w-O-酯化反应，从而导致酰基Cer的产生。然而，目前尚不清楚乙酰胆碱缺乏的基础，也不知道乙酰胆碱缺乏对阿尔茨海默病发病的作用。我们假设在AD时，酰基Cer的合成减少或加速了水解率。这种生化异常可以归因于T辅助细胞2(Th2)细胞因子诱导的下调和/或干旱应激分别通过外部湿度感受器和渗透压感受器(TRPV4和TONEBP)介导的异常信号。综上所述，这些信号缺陷导致了AD中酰基Cer的缺失。我们将研究1)AcylCer缺乏的酶(关键酶/辅因子，即ELOVL4、w-羟基酶、AWAT1和CGI-58)基础以及AcylCer缺乏在AD中的结构/功能后果；2)Th2细胞因子如何下调AD中的AcylCer；3)干旱应激如何通过TRPV4受体和/或TONEBP信号调节AcylCer的合成及其在AD中的变化；以及4)AD中AcylCer恢复的新治疗策略。 公共卫生相关性： 项目简介：人们越来越多地接受特应性皮炎(AD)的主要屏障缺陷，这种疾病表现为选择性酰神经酰胺(AcylCer)缺乏，导致 经皮肤暴露于可诱发AD的过敏原，并刺激AD进展为哮喘和过敏性鼻炎。从拟议的研究中获得的见解将确定AD的新治疗形式，AD是退伍军人中的一种常见疾病，其基础是使用适当的代谢前体使酰基Cer水平正常化或刺激内源性酰基Cer的产生。